Progesterone plays a major role in reproductive health and functioning, and its effects on, for example, the uterus, breast, cervix and hypothalamic-pituitary unit are well established. It also has extra-reproductive activities that are less well studied, such as effects on brain, immune system, vascular endothelial system and lipid metabolism. Given this wide array of effects, it is apparent that compounds which mimic some of the effects of progesterone (agonists), antagonize these effects (antagonists) or exhibit mixed effects (partial agonists or mixed agonist/antagonist) can be useful in a variety of diseases and conditions.
Steroid hormones exert their effects in part by binding to intracellular receptors.
Compounds that bind to the appropriate receptors and are antagonists or partial agonists of the estrogenic and androgenic hormones have long been known, but it was not until around 1982 that the discovery of compounds that bind to the progesterone receptor and antagonize the effects of progesterone was announced. Since then, a number of such compounds have been reported in the scientific and patent literature and their effects in vitro, in animals and in humans have been studied. Although compounds such as estrogens and certain enzyme inhibitors can prevent the physiological effects of endogenous progesterone, in this discussion "antiprogestin" is confined to those compounds that bind to the progestin receptor.
Information indicating that antiprogestins would be effective in a number of medical conditions is now available. This information has been summarized in a report from the Institute of Medicine (Donaldson, Molly S.; Dorflinger, L.; Brown, Sarah S.; Benet, Leslie Z., Editors, Clinical Applications of Mifepristone (RU 486) and Other Antiprogestins, Committee on Antiprogestins: Assessing the Science, Institute of Medicine, National Academy Press, 1993). In view of the pivotal role that progesterone plays in reproduction, it is not surprising that antiprogestins could play a part in fertility control, including contraception (long-term and emergency or post-coital), menses induction and medical termination of pregnancy, but there are many other potential uses that have been supported by small clinical or preclinical studies. Among these are the following:
1. Labor and delivery--antiprogestins may be used for cervical ripening prior to labor induction such as at term or when labor must be induced due to fetal death. They may also be used to help induce labor in term or post-term pregnancies.
2. Treatment of uterine leiomyomas (fibroids)--these non-malignant tumors may affect up to 20% of women over 30 years old and are one of the most common reasons for surgery in women during their reproductive years. Hysterectomy, the common treatment for persistent symptoms, of course results in sterility.
3. Treatment of endometriosis--this common (5 to 15% incidence, much larger in infertile women) and often painful condition is now treated with drugs such as danazol or gonadotrophin-releasing hormone analogs that have significant side-effects, or must be dealt with surgically.
4. Cancers, particularly breast cancers--the presence of progestin receptors in many breast cancers has suggested the use of antiprogestins in treating metatstatic cancer or in prevention of recurrence or initial development of cancer.
5. Other tumors such as meningiomas--these brain membrane tumors, although non-malignant, result in death of the patient and nonsurgical treatments are lacking.
6. Male contraception--antiprogestins can interfere with sperm viability, although whether this is an antiprogestational effect or not is controversial, as it may relate to the antiglucocorticoid activity of such compounds.
7. Antiestrogenic effects--at least some antiprogestins oppose the action of estrogens in certain tests, but apparently through a mechanism that does not involve classical hormone receptors. This opens a variety of possibilities for their medical use.
8. Antiglucocorticoid effects--this is a common side-effect of antiprogestins, which can be useful in some instances, such as the treatment of Cushing's syndrome, and could play a role in immune disorders, for example. In other instances it is desirable to minimize such effects.
9. Hormone replacement therapy--the ability to antagonize the actions of progestins is valuable for use in this area.
The effects and uses of progesterone agonists have been well documented. In addition, it has been recently shown that certain compounds structurally related to the known antiprogestins have strong agonist-like activity in certain biological systems (e.g., the classical progestin effects in the estrogen-primed immature rabbit uterus; cf. C. E. Cook et al., Life Sciences, 52, 155-162 (1993)). Such compounds are partial agonists in human cell-derived receptor systems, where they bind to a site distinct from both the progestin and antiprogestin sites (Wagner et al., Proc. Natl. Acad. Sci., 93, 8739-8744 (1996)). Furthermore the interaction of the receptor/drug complex with the genome can vary from class to class of antiprogestins--either binding to the genome may occur with no transcriptional result or the antiprogestin may prevent binding of the complex to the genome. Thus the general class of antiprogestins can have many subclasses, which may vary in their clinical profiles.
In spite of the clinical promise of antiprogestins, as of Mar. 1, 1999, there were no antiprogestin drugs marketed in the United States or many other countries. Only one antiprogestin drug is approved and available for clinical use anywhere in the world and that drug, mifepristone, is mainly used for medical termination of pregnancy. A number of factors are the cause of this situation, but certainly a need exists for new antiprogestational drugs that can be used for the conditions described above. It is one purpose of this invention to provide such drugs.
Generally antiprogestational activity has been associated with the presence of an 11.beta.-aryl substituent on the steroid nucleus, together with a .DELTA..sup.4,9 -3-ketone moiety. The earliest antiprogestins were substituted with a 17.beta.-hydroxyl group and various 17.alpha.-substituents. (See for example, Teutsch et al. U.S. Pat. No. 4,386,085 Philibert et al. U.S. Pat. No. 4,477,445; Teutsch et al. U.S. Pat. No. 4,447,424; Cook, et al. U.S. Pat. Nos. 4,774,236 and 4,861,763. Then it was discovered that a 17.beta.-acetyl-17.alpha.-acyloxy group could also generate antiprogestational effects (Cook et al. U.S. Pat. Nos. 4,954,490 and 5,073,548) and various permutations of these findings have been made as well. However, introduction of a 16.alpha.-ethyl group or a hydrogen substituent at the 17.alpha.-position in the 17.beta.-acyl series of 11.beta.-aryl compounds leads to agonist or partial agonist activity (C. E. Cook et al., Life Sciences, 52, 155-162 (1993)). Other reports in the area of antiprogestational compounds include Teutsch. et al. Human Reproduction. Jun. 9, 1994 (Supplement 1): 12-31 and Cook et al. Human Reproduction. Jun. 9, 1994 (Supplement 1):32-39. Thus changes in the D-ring of the steroid can result in unpredictable effects on the biological activity.
17-thio-substituted steroids have been reported in the literature. (e.g. Smith et al. Journal Biological Chemistry. 1974; 249(18):5924-5932; Varma U.S. Pat. No. 4,481,144; and Varma et al., U.S. Pat. No. 4,529,548.
It can be seen that the 17.beta.-position of already known antiprogestins has been characterized by substitution with a carbon or an oxygen atom. No reports have been made of the effect of thio substituents such as 17,17-spirothiolanes in the 17.beta.-position of 11.beta.-aryl steroids on their hormonal or antihormonal activity. Until the current invention there existed no methods for their synthesis. No 17,17-spirothiolane steroids have been found in either the general chemical literature or in patents. The prior art thus does not permit a prediction regarding the activity of such compounds. One novel feature of the present invention is the finding that a spiro[17,17'-2'-thiolane] in 11.beta.-aryl steroids result in compounds with good binding to the progestin receptor.
It is therefore the purpose of the present invention to provide novel and potent progestin receptor response modulators, to provide methods for their medical use in mammals, including humans, and to provide methods for their synthesis.